Calcium is an essential nutrient and the most abundant mineral in the human body. Calcium plays a vital role in building healthy teeth and bones, blood clotting, muscle contraction, and nerve function. Most notably, calcium reduces the risk of bone loss caused by osteoporosis in both men and women. Despite these advantages, it has been estimated that half of all Americans do not consume sufficient amounts of calcium. More troubling, 80% of women, the group at highest risk for developing osteoporosis, do not consume enough calcium.
This deficiency is due in part to the large daily intake of calcium that is suggested by physicians. The National Academy of Sciences, Institute of Medicine recommends daily intakes (RDI) of 1,200 mg of elemental calcium per day for people over 50 years of age and 1,300 mg a day for people under 19 years of age. For individuals between these age groups, the recommendation is 1,000 mg per day. Not surprisingly, physicians recommend calcium supplements more than any other dietary supplement.
Commercially available calcium supplements employ a wide variety of calcium salts, including, for example, calcium carbonate, calcium citrate, calcium glycerophosphate, calcium oxide, calcium phosphate, calcium pyrophosphate, calcium chloride, calcium lactate, and calcium sulfate. Despite the very different solubilities of these salts, their absorption in the intestine is comparable. For example, while calcium carbonate is insoluble in water and calcium citrate is soluble, isotopic tracer methods have established that their bioavailability is similar. In view of the similar bioavailability of various calcium salts, calcium carbonate has become the most common salt for supplementation because it is comparably inexpensive and delivers more elemental calcium on a weight basis (˜40%) than most other calcium salts. However, the absorption of calcium carbonate through the intestine, like all calcium salts, is relatively inefficient. For example, it has been reported that calcium carbonate absorption efficiency is about 34.2%±10.1% in adult men and postmenopausal women. See Heaney, R. P. et al., “Absorption of calcium as the carbonate and citrate salts, with some observations on method.” Osteoporos. Int. 9:19-23 (1999).
Vitamin D is known to be a beneficial adjunct to calcium supplementation because it both increases absorption efficiency up to a serum 25-OH vitamin D level of 80 nmol/ml and regulates parathyroid hormone levels which in turn regulate bone absorption/resorption of calcium. The amino acid L-lysine has also been reported to enhance calcium absorption efficiency in humans and rats. See Civitelli et al. “Dietary L-lysine and calcium metabolism in humans,” Nutrition 8: 400-5 (1992); Wasserman et al. “Interrelated effects of L-lysine and other dietary factors on the gastrointestinal absorption of Calcium 45 in the Rat and Chick.” J. Nutrition 62, 367-376 (1957). However, the efficacy of L-lysine supplementation has not been established in chronic feeding. Despite the benefits of calcium supplements, particularly those fortified with Vitamin D, it would be desirable to provide a form of calcium for use in calcium supplements and food products having improved absorption characteristics.
It is known in the pharmaceutical industry that an important factor which effects the bioavailability of a drug is particle size. There is generally an inverse relationship between the particle size of nonionized particles and absorption through the gut. See Florence et al., “Factors Affecting the Oral Uptake and Translocation of Polystyrene Nanoparticles: Histological and Analytical Evidence,” J. Drug Target 3, 65-70 (1995). A recent in vitro study showed cellular uptake was greater for polystyrene particles in the 100-200 nm size range than for similar smaller or larger particles. Win et al. “Effects of Particle Size and Surface Coating on Cellular Uptake of Polymeric Nanoparticles for Oral Delivery of Anticancer Drugs,” Biomaterials 26, 2713-22 (2005).
However, The effect of particle size on calcium absorption has received only modest attention to date. Rao et at studied the effect of limestone calcium carbonate particle size on in vivo solubilization and retention in hens. See K. S. Rao et al., “In Vivo Limstone Solubilization in Commercial Leghorns: Role of Dietary Calcium Level, Limestone Particle Size, In Vitro Limestone Solubility Rate, and the Calcium Status of the Hen,” Poultry Sci., 69:2170-2176 (1990). The authors report that hens consuming calcium carbonate of particle size between 2 and 5 mm (millimeters) solubilize and retain a greater percentage of calcium than hens fed calcium carbonate of particle size between 0.5 and 0.8 millimeters. The authors state that this is consistent with their earlier finding that hens fed large particulate limestone retain a greater percentage of calcium than hens fed small particulate limestone, Rao et al, “Influence of Dietary Calcium Level and Particle Size of Calcium Source on In Vivo Calcium Solubilization by Commercial Leghorns,” Poultry Sci. 68:1499-1505 (1989). It is suggested that greater utilization of large particles of calcium carbonate as compared to small particles results from an increased residence time in the gizzard which provides for gradual metering through the intestine, as previously posited by Scott et al, “The Calcium Requirements of Laying Hens and Effects of Dietary Oyster Shell Upon Eggshell Quality,” Poultry Sci. 50:1055-1063 (1971). In contrast, Guinotte and coworkers report that ground calcium carbonate having a particle size less than 0.15 mm improved calcium retention and tibial ossification in growing chicks as compared to medium (0.3 to 1.18 mm) and large (1.18 to 4.75 mm) calcium carbonate particles. See F. Guinotte et al., “The Effects of Particle Size and Origin of Calcium Carbonate on Performance and Ossification Characteristics in Broiler Chicks,” Poultry Sci., 70:1908-1920 (1991). Similar studies on particle size and absorption in humans or rodents are lacking.
There is continuing need in the art for calcium forms having high in vivo utilization efficiency. It therefore is an object of the present invention to identify critical parameters of calcium carbonate powders which provide for enhanced bioavailability and to provide such powders. It is another object of the present invention to provide dietary supplements, foods and the like comprising highly absorbable calcium forms. It is also an object of the invention to provides compositions and methods for increasing calcium balance. It is further an object of the invention to provide composition and methods for preventing, treating, and/or ameliorating the effects of osteoporosis with calcium supplements, ideally without resort to pharmaceutical intervention.